Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk

Abstract

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361–0.7719 and OR 0.1522; 95% CI 0.02941–0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

Pathophysiology of Chronic Liver Disease Development

“…In line with previous studies, the heterozygous Pi*MZ genotype was overrepresented in the cirrhotic subjects compared to controls, while the occurrence of the genotype Pi*MS did not differ significantly [ 11 , 12 ]. In contrast, both genotypes were less common in cirrhotics with HCC compared to the ones without [ 11 ]. While an independent confirmation is needed, these data might be useful for clinical management and counseling of these individuals.…”

“…Last but not least, Rabekova et al took advantage of a large cohort of patients with liver cirrhosis and studied whether genetic variants in the alpha1-antitrypsin gene affect the susceptibility to development of HCC [ 11 ]. In line with previous studies, the heterozygous Pi*MZ genotype was overrepresented in the cirrhotic subjects compared to controls, while the occurrence of the genotype Pi*MS did not differ significantly [ 11 , 12 ]. In contrast, both genotypes were less common in cirrhotics with HCC compared to the ones without [ 11 ].…”

Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

“…Given that liver cirrhosis constitutes an increased risk for HCC, we advocate for HCC screening for all AATD patients with cirrhosis, irrespectively of their genotype. With regard to the latter, Pi*SZ subjects seem to carry a ~7times increased HCC risk [45], while Pi*MZ individuals do not and might in fact be even protected from HCC [45,56]. This somewhat puzzling observation might be related to the fact that Pi*MZ with liver cirrhosis decompensate/die faster than individuals without AAT variants [57,58].…”

“…With regard to the latter, Pi à SZ subjects seem to carry an approximately seven times increased HCC risk, 45 while Pi à MZ individuals do not and might in fact be even protected from HCC. 45,56 This somewhat puzzling observation might be related to the fact that Pi à MZ with liver cirrhosis decompensate/die faster than individuals without AAT variants. 57,58 While the rate of decompensation in other genotypes remains unknown, it is expected to be also accelerated 59 and because of that, AATD patients with cirrhosis should be evaluated for liver transplantation early on.…”

Heat Shock Transcription Factor 2 Is Significantly Involved in Neurodegenerative Diseases, Inflammatory Bowel Disease, Cancer, Male Infertility, and Fetal Alcohol Spectrum Disorder: The Novel Mechanisms of Several Severe Diseases

“…SERPINA1 (Serpin family A member 1) encodes a well-known elastase inhibitor, alpha-1 antitrypsin (AAT). Previously, Wiseman and his colleagues reported that SERPINA1 can be diagnostic biomarker of thyroid cancer [ 112 ], and SERPINA1 has been recently reported to be involved in several other cancers including gastric, liver, pancreas, breast, lung, and ovarian cancers [ 113 , 114 , 115 , 116 , 117 , 118 ]. Moreover, Gao and his colleagues suggested that SERPINA1 is one of key genes in brain metastasis from lung adenocarcinoma [ 119 ].…”